1. Field of the Invention
The invention relates to the field of pharmaceutical and organic chemistry and pertains to a process for anomerizing nucleosides.
2. State of the Art
Processes for preparing nucleosides frequently result in a mixture of alpha and beta nucleoside anomers. These nucleoside anomers are typically separated by a physical means such as crystallization or chromatography. Most often, the desired biological activity of a nucleoside resides predominantly in a single anomer of an anomeric mixture. However, the amount of a specified nucleoside anomer recoverable from an anomeric mixture by the above mentioned separation methods is often substantially less than that originally present in the anomeric mixture. Such low recoveries are generally due to interference from increased proportions of the unwanted anomer as the separation proceeds. Beta nucleoside anomers are useful and important as pharmacologically active compounds. Anomerization provides a way of increasing the amount of a desired nucleoside anomer over that originally present in an anomeric mixture. When used in conjunction with the aforementioned separation methods, anomerization can afford substantially improved overall recoveries of a desired nucleoside anomer.
Nucleoside anomerization has been accomplished by photoirradiation in water, see R. A. Sanchez, et al., J. Mol. Biol., 47, 531-543 (1970); and with bromine, see H. Quelo, et. al., C. R. Acad. Sci., Ser. C, 275, 1137-1140 (1972).
J. Cadet, et al., describe nucleoside anomerization in "Nucleic Acid Hydrolysis I. Isomerization and Anomerization of Pyrimidic Deoxyribonucleosides in an Acidic Medium.", J. Amer. Chem. Soc., 96:20, 6517-6519 (1974) which involves contacting thymidine and 2'-deoxyuridine nucleosides with 2M HClO.sub.4 at 90.degree. C. to make .alpha.- and .beta.-furanosidic and pyranosidic anomers.
Yamaguchi, T., et. al., in "Synthetic Nucleosides and Nucleotides. XXI. On the Synthesis and Biological Evaluations of 2'-Deoxy-alpha-D-ribofuranosyl Nucleosides and Nucleotides", Chem. Pharm. Bull., 32(4), 1441-1450 (1984) describe anomerizing .beta.-3',5'-di-O-p-toluoyl-2'-deoxythymidine and .beta.-N.sup.4 -benzoyl-2'-deoxycytidine with bis(trimethylsilyl)acetamide and trimethylsilyltrifluoromethanesulfonate in dry acetonitrile at 70.degree. C.
Nucleoside anomerization employing protic acids or Lewis acids have been applied to a wide variety of nucleosides and include for example: 2M HCl, see F. Seela and H. D. Winkler, Carbohydrate Research, 118, 29-53 (1983); 1M HBr, see J. Cadet, Tetrahedron Lett., 867-870 (1974); and NaI/HOAc, see J. Matulic-Adamic, et. al., J. Chem. Soc., 2681-2686 (1988).
Base catalyzed anomerization has also been reported. For example, Armstrong, V. W., et al., in "The Base Catalyzed Anomerization of .beta.-5-Formyluridine; Crystal and Molecular Structure of .alpha.-5-Formyluridine", Nucleic Acid Res., 3, 1791 (1976) describe the treatment of .beta.-5-formyluridine with 1:1 4N aqueous NaOH:MeOH at room temperature which affords an anomerically mixed product. However, uridine and 5-bromouridine are not anomerized by this process since they lack the 5-formyl group on the nucleoside substrate. I., Hideo, et al., "Synthesis of 5-Alkyl and 5-Acyl-uridines via 6-Mercaptouridine (Nucleosides and Nucleotides XVII)", Heterocycles, 8, 427-432 (1977) describe the anomerization of 2',3'-O-isopropylidene-5-acetyl-.alpha.-uridine with 2N sodium hydroxide. As can be seen, base catalyzed anomerization has been limited to pyrimidine nucleosides having electron-withdrawing substituents (e.g. formyl or acetyl groups) at the C-5 position of the heterocyclic portion of the nucleoside.
An object of the present invention is to provide a base catalyzed process for anomerizing nucleosides.
Another object of this invention is to provide a base catalyzed process for anomerizing 2'-deoxy-2',2'-difluoro-nucleosides.
Another object of this invention is to provide a base catalyzed process for anomerizing alpha-anomer-enriched nucleosides free of the disadvantages and limitations found in the prior art.
Another object of this invention is to provide a base catalyzed process for anomerizing beta-anomer-enriched nucleosides free of the disadvantages and limitations found in the prior art.